Recent studies have suggested that successful antitumor responses consisted of a combination of T cell-mediated and non-T cell-mediated mechanisms. We have used transplantable mouse renal and autochthonous mammary carcinoma models to demonstrate that the systemic administration of the combination of IL-2 + IL-12 yields enhanced antitumor effects against even well-established metastatic cancers. Further, the local injection of replication-defective pox viruses (pv) modified to express Il-12 also induces potent antitumor effects against transplantable renal and lung tumors. The mechanism for these effects is complex, and depends on the presence of CD8 positive T cells for induction of the response. However, the effector phase occurs in the absence of a large accumulation of T cells at the tumor site; but does coincide with the development of anti-neovascular effects, enhanced induction of chemokines and Th1 cytokines, reduced production of Th2 cytokines, and a reversal of the tumor-induced inhibition of nitric oxide production. In addition, the systemic (IV) administration of pv IL-12 + systemic IL-2 is able to reduce the number of pre-existing hepatic metastases by about 95%. Additional studies have shown that the recruitment of antitumor effector NK and T cells to tumors may be impaired because of inappropriate expression of the requisite adhesion molecules in tumor neovasculature. However, our studies also have shown for the first time that the cytokine-induced redistribution of NK cell to parenchymal organs that are often the site of metastases formation are critically dependent on the interaction of the VCAM-1/VLA-4 adhesion/ligand pair. Further, the results have shown that IL-2 and IL-12 differentially regulate the recruitment of NK vs T cells to the liver. Overall, these results demonstrate that the successful induction and mediation of antitumor effects results from complex events that depend on both T cell-mediated and T cell-dependent, non-T cell-mediated processes. By understanding the relative contributions of these different, but related processes, we should gain new insight into biological mechanisms that can be exploited for the treatment of cancer.